Stimulation of the forno-dorso-commissure (fdc) for seizure suppression and memory improvement

ABSTRACT

Example apparatus and methods cause activation of target neural tissue through electrical stimulation of a connected white matter tract to reduce the hyper-excitability of the target neural tissue and thus reduce seizures while preserving memory in humans. Example apparatus and methods apply low frequency (e.g., &lt;10 HZ) electrical stimulation to the forno-dorso-commissure (FDC), detect an electrical signal generated in an area connected to, innervated by, or that can be activated by the FDC in response to the stimulation, and reconfigure the stimulation based on the detected signal and a desired therapeutic effect. The stimulation may be reconfigured to produce an electrical stimulation waveform that will produce the desired therapeutic effect. The desired therapeutic effect may be, for example, reducing hyper-excitability of neural tissue in a target area, reducing hippocampal spikes, reducing seizure odds, or improving recall.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/753,503 filed Jan. 17, 2013 and U.S. Provisional Application61/912,378 filed Dec. 5, 2013.

BACKGROUND

Temporal lobe epilepsy is the most common focal epilepsy in adolescentsand adults, and the most frequent indication for epilepsy surgery.Mesial temporal lobe epilepsy (MTLE) often originates from thehippocampus, which is implicated in declarative memory function. Aclinical trial in patients with intractable MTLE showed that temporallobectomy is superior to continued medical therapy in achieving seizurefreedom. However, resection is generally eschewed if pre-surgicalevaluation predicts functional deficits. Additionally, more than half ofall intractable patients are not candidates for surgical resection. Therisk of memory decline after hippocampal resection depends on thestructural integrity of the hippocampus and its degree of contributionto memory function prior to surgery. A non-lesional, language dominanthippocampus and good preoperative memory function often exclude MTLEpatients from temporal lobectomy because of the high-risk ofpostoperative memory decline. This underlies the need to pursuecontrolling disabling hippocampal seizures without compromising memoryfunction.

While surgical resection of the temporal lobe is an effective treatmentfor medically-intractable temporal lobe epilepsy, surgical resectionoften results in memory impairment. Thus, other approaches includingdeep brain stimulation (DBS) have been undertaken. DBS in epilepsy hastargeted gray matter structures using high frequencies, but has notachieved desired results. Conventional DBS may provide a firststimulation when there is no prediction of an impending seizure but mayprovide a second altered stimulation based on a prediction of animpending seizure, where the prediction is based on monitoring naturallyoccurring, organically generated signals. For example, conventionalsystems may be programmed to detect and record seizure activity based onsignals generated naturally in the brain by the brain itself.Conventional systems may also be configured to control stimulation as afunction of the detected or recorded seizure activity.

DBS has risen as an effective treatment in patients with movement orpsychiatric disorders. The stimulation targets specific areas in thebrain, altering the function of circuits or inducing neurogenesis andother plastic changes. DBS has been approved for treatment ofParkinson's disease, essential tremor, dystonia, andobsessive-compulsive disorder, but its success in epilepsy has beenlimited. Most stimulation trials in epilepsy have used high frequencies.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate various example systems, methods,and other example embodiments of various aspects of the invention. Itwill be appreciated that the illustrated element boundaries (e.g.,boxes, groups of boxes, or other shapes) in the figures represent oneexample of the boundaries. One of ordinary skill in the art willappreciate that in some examples one element may be designed as multipleelements or that multiple elements may be designed as one element. Insome examples, an element shown as an internal component of anotherelement may be implemented as an external component and vice versa.Furthermore, elements may not be drawn to scale.

FIG. 1 illustrates a pre-operative brain magnetic resonance imaging(MRI) image co-registered with a postoperative computed tomography (CT)scan showing the location of depth electrodes in theforno-dorso-commissural (FDC) tract and the body of the fornix.

FIG. 2A illustrates locations of forno-dorso-commissural electrodes in asubject in sagittal and coronal views where 1 Hz stimulation wasapplied, a hippocampal electrode where the evoked response was recorded,and a graph of a hippocampal evoked response.

FIG. 2B illustrates evoked potentials detected in the hippocampus andposterior cingulate gyms, with respective peaks at 36 and 187 msec, inresponse to a 1-Hz stimulation of the fornix.

FIG. 2C is a coronal MRI that shows the location of an electrode in thehippocampal body where responses with maximal voltages were recorded.

FIG. 2D is a coronal MRI that shows the location of an electrode in theposterior cingulate gyms where responses with maximal voltages wererecorded.

FIG. 3 illustrates hippocampal spike counts averaged per hour before,during, and after low-frequency stimulation.

FIG. 4 illustrates a scatter plot showing seizures recorded before andafter example stimulation.

FIG. 5 illustrates results from a series of stimulation sessions for apatient.

FIG. 6 illustrates the location of an FDC.

FIG. 7 illustrates an example method associated with achieving a desiredtherapeutic effect by controlling stimulation of the FDC based on thesignal evoked in response to stimulating the FDC.

FIG. 8 illustrates an example apparatus associated with achieving adesired therapeutic effect by controlling stimulation of the FDC basedon the signal evoked in a target area in response to stimulating theFDC.

FIG. 9 illustrates an example apparatus associated with achieving adesired therapeutic effect by controlling stimulation of the FDC basedon the signal evoked in a target area in response to stimulating theFDC.

DETAILED DESCRIPTION

Example apparatus and methods cause activation of target neural tissue(e.g., amygdala, hippocampus, posterior cingulate gyms) throughelectrical stimulation of a connected white matter tract. Thestimulation and resulting evoked response reduce the hyper-excitabilityof the target neural tissue which may in turn reduce interictalepileptiform discharges and seizures while preserving memory in humans.Example apparatus and methods apply low frequency (e.g., <10 HZ)electrical stimulation to the forno-dorso-commissure (FDC) in patientsimplanted with depth electrodes, detect an electrical signal generatedin response to the stimulation, and reconfigure the stimulation based onthe detected signal and a desired therapeutic effect. The electricalsignal is detected in a target area that is connected to the stimulatedwhite matter, innervated by the stimulated white matter, or that can beactivated by stimulating the white matter.

Surgical resection of the temporal lobe is an effective treatment formedically-intractable temporal lobe epilepsy, but often results inmemory impairment. Deep brain stimulation (DBS) to treat epilepsy hastargeted gray matter structures using high frequencies. But highfrequencies have not produced desired results and may produce undesiredside-effects. Experiments in animals have shown that low frequencystimulation can delay epileptogenesis. Experiments have also shown thatlow frequency stimulation applied to a white matter tract can reduceseizure in different animal models of MTLE. Thus, example methods andapparatus concern low-frequency stimulation of white matter (e.g., FDC)to reduce hyper-excitability of target neural tissues which may in turnreduce interictal epileptiform discharges and seizures in patients withintractable mesial temporal lobe epilepsy. After stimulating whitematter, a resulting electrical signal is measured in a target area inthe brain. The target area is connected to, innervated by, or can beactivated by the white matter. The resulting electrical signal is not anaturally occurring signal but rather is caused by and is a function ofthe stimulation.

Conventional stimulation studies in epilepsy have used high-frequenciesof 100-165 Hz and found limited benefit in reducing seizures. Possiblemechanisms of action of high-frequency stimulation include activation ofpresynaptic inhibitory inputs and activation of efferent projections,reducing deleterious signals in neural circuits by reducing “informationcontent.” Activation of efferent projections may affect the properfunctioning of the stimulated brain structure and produce alterations inmemory processing observed during direct stimulation of the hippocampusat either high or low frequencies. Direct hippocampal stimulation isspatially limited and results in only limited benefit as regards seizurereduction. But direct hippocampal stimulation has been shown tointerfere with memory processing at either high or low frequencies.Unlike direct hippocampal stimulation, stimulation of hippocampalafferents may produce fewer disruptive effects on memory becauseafferent tract stimulation spares hippocampal interneurons and glia fromdirect activation. Instead, afferent tract stimulation activates ahomogeneous neuronal population, such as dentate granule cells, as withentorhinal stimulation, or pyramidal cells, as in fornix stimulation.Low frequency stimulation can inhibit abnormal excitatory activity byincreasing the threshold of action potential firing by long termdepression, or increasing gamma-aminobutyric acid (GABA) mediatedinhibition. These mechanisms are different from those of high frequencystimulation, and may not only reduce seizures, but remodel the tissue ina manner that improves functional deficits related to theepileptogenicity of a particular brain region. Indeed, low-frequencystimulation of either the kindling focus or areas that participate inseizure spread delays seizure development in a hippocampal epilepsymodel in rats. Even in fully kindled animals, preemptive low frequencystimulation at the hippocampal commissure dramatically decreases stage 5seizures.

Example apparatus and methods treat patients suffering from epilepsy. Inone embodiment, apparatus and methods may treat mesial temporal lobeepilepsy. Experiments in human patients have shown that stimulation atthe FDC reduces interictal epileptiform discharges and seizures inpatients with intractable mesial temporal lobe epilepsy. The reductionmay be due to increasing a threshold of action potential firing in theneural tissue in the target area by long term depression, or byincreasing GABA-mediated inhibition in the neural tissue in the targetarea. The FDC is an area that is anterolateral to the splenium of thecorpus callosum where the crux of the fornix travels with fibers of thedorsal hippocampal commissure. In one embodiment, an electrode islocated as shown in FIG. 6. In different embodiments, a single electrodemay be placed unilaterally or two electrodes may be placed bilaterally.

FIG. 1 illustrates a pre-operative brain MRI co-registered withpostoperative CT scan showing the location of depth electrodes in theforno-dorso-commissural tract at the intersection of lines 100 and 120and lines 110 and 130. FIG. 1 also shows the location of depthelectrodes in the body of the fornix at the intersection of lines 110and 120 and at the intersection of lines 110 and 130.

FIG. 2A provides sagittal and coronal views of locations of theforno-dorso-commissural electrodes in a subject. The electrodes includean electrode in the FDC where 1 Hz stimulation was done and thehippocampal electrode where an evoked response was monitored. Ahippocampal evoked response is shown at 17 msec following 1 Hzstimulation.

FIG. 2B illustrates evoked potentials recorded in the hippocampus andposterior cingulate gyms. Potentials may be recorded in other targetareas (e.g., amygdala). FIG. 2B shows peaks at 36 msec for the potentialevoked in the hippocampus and peaks at 187 msec for the potential evokedin the posterior cingulate gyms. The peaks were produced using 1-Hzstimulation of the fornix.

FIG. 2C is a coronal MRI that shows the location of an electrode in thehippocampal body where responses with maximal voltages were recordedafter stimulation performed using the electrode illustrated in FIG. 2A.

FIG. 2D is a coronal MRI that shows the location of an electrode in theposterior cingulate gyms where responses with maximal voltages wererecorded after stimulation performed using the electrode illustrated inFIG. 2A.

The fornix has approximately 1.2 million fibers. These include fibersthat originate in the hypothalamus and other subcortical structures andthat terminate in the hippocampus and parahippocampus. The fornix alsoincludes fibers that travel in the opposite direction, originating inthe subiculum, CA3 region of the hippocampus, entorhinal cortex, andparahippocampal gyms. The fornix enables the transmission of informationascending to the brainstem to influence the functioning of the limbicsystem, and may mediate some of the autonomic symptoms of MTLE seizuresby connecting the hippocampus with the hypothalamus. The role of thefornix in memory is well-established. For example, high frequencystimulation of the fornix results in vivid recollection of past events,and bilateral fornicotomy causes amnesia.

In different experiments, depth electrodes were implanted in patients inthe FDC for surgical evaluation of intractable epilepsy. Low frequencystimulation occurred in four-hour sessions. In different examples,stimulation may be performed in sessions of different duration. During asession, the stimulation was provided continuously at an applicationfrequency (e.g., 1 Hz). Mental status assessment was performed atbaseline and during stimulation. The effect of stimulation onhippocampal spikes and seizures was measured.

Stimulation of the FDC elicited evoked responses in the hippocampus andthe posterior cingulate gyms. Responses may also be evoked in otherareas (e.g., amygdala). Hourly mini-mental status examination scoresshowed an increase during stimulation, largely due to improvement inrecall. Hippocampal spikes were reduced during and outlasting eachstimulation session.

FIG. 5 illustrates hippocampal spikes per hour for a patient during andafter stimulation with different frequency. The reduction in seizuresand hippocampal spikes are the result of reducing the hyper-excitabilityof neural tissue that is innervated by, connected to, or activated bythe stimulation site.

Stimulation of the FDC tract site activates the hippocampus and otherareas of the declarative memory circuit and default mode network.Stimulation of the FDC is tolerable and reduces epileptiform dischargesand seizures in patients with intractable mesial temporal lobe epilepsy.In one embodiment, FDC tract stimulation may improve memory in patientswith Alzheimer's disease, hippocampal sclerosis, autism, schizophreniaor stroke. In another embodiment, FDC tract stimulation may improvememory in patients with memory disorders including, but not limited to,psychiatric or cognitive disorders and senile dementia.

Fornix stimulation elicited evoked responses in the hippocampus and theposterior cingulate gyms. Thus, example systems and methods monitorresponses evoked by stimulation rather than making predictions based onnaturally occurring signals. Stimulation of the white matter tract maybe done by placing an electrode directly into the tract and stimulating.The amplitude of the stimulus can be adjusted and the amplitude of thestimulation produced may be monitored or recorded. For example, anevoked potential in a connected area may be monitored or recorded. Indifferent embodiments, the stimulus can be adjusted to generate betweenzero percent and one hundred percent of the evoked potential amplitudenecessary to generate a desired therapeutic effect. The stimulus can beadjusted. For example, a monitoring or recording electrode may belocated in a target nucleus innervated by the white matter tract beingstimulated. A feedback loop may be established to control thestimulation level. The stimulation level may be adjusted to control theamplitude of the evoked potential during the stimulation period tomaintain or achieve the desired therapeutic outcome. The stimulationlevel may be controlled by adjusting the current, voltage, or otherparameter (e.g., waveform) of the stimulation.

Example apparatus and methods may be decoupled from directly detectingor recording seizure activity based on naturally occurring signalsgenerated by the brain. Instead, example apparatus and methods maycontrol stimulation based on analyzing the results of signals generatedby the example apparatus and methods. Instead of detecting or recordingseizure activity as a function of signals generated by the brain,example apparatus and methods monitor the response(s) generated bystimulation. For example, a stimulation may be produced and theamplitude of the response generated by the stimulation may be measured.When no seizure is imminent, the amplitude of the response generated bythe stimulation may fall within a first range. When a seizure isimminent, the amplitude of the response generated by the stimulation mayfall within a second different range. When the response generated by thestimulation falls within the second, different range, example apparatusand methods may control the stimulation to mitigate or prevent aseizure. In another embodiment, the frequency content may have specificcharacteristics that differ before the seizure is imminent from when theseizure is not imminent. In another embodiment, the shape of the evokedresponse measured by conventional signal processing technique (e.g.,half-width duration, rise/fall time) may vary before a seizure isimminent from when it is not imminent. The amplitude, frequency content,shape, or other property of the response may be a function of propertiesof tissue in the target area that are affected by a seizure precursor.

Conventional systems may have attempted to detect an impending epilepticseizure based on signals generated in the brain by the brain. Exampleapparatus and methods apply low frequency stimulation to a stimulationsite (e.g., hippocampal commissure) to cause an evoked potential in oneor more target areas. The potential that is evoked in a target area maydepend, at least in part, on whether a seizure is imminent. Bio-chemicalor bio-electrical changes associated with an impending seizure may causethe evoked potential to vary. The signal being examined to determinewhether a seizure is imminent is a signal produced in response tostimulation, it is not a naturally occurring signal.

In one example, the amplitude of a response evoked in a target region ismonitored and may be recorded. The amplitude of the response may varybased on the excitability of the tissue. For example, when a seizure isimminent, the excitability of the tissue may increase. If theexcitability increases then the amplitude of the evoked response mayalso increase. Example apparatus and methods may monitor the amplitudeof the evoked response and selectively alter the stimulation provided tothe stimulation site (e.g., white matter tract, FDC, hippocampalcommissure) as a function of the detected amplitude.

In another example, the monitoring or recording electrode may be used tomonitor the impedance of the tissue in the target region. A lowamplitude signal may be passed into the tissue around the electrode andthe impedance measured. The low amplitude signal may be, for example, asinusoidal signal. When a seizure is imminent, the impedance may changein a detectable way. When the change in impedance is detected, thestimulation provided may be selectively altered to mitigate or preventthe seizure. Once again, rather than rely on signals that are beinggenerated organically in the brain, example apparatus and methods maygenerate signals that produce different measurable results when aseizure is imminent. Characteristics or properties of the stimulation(e.g., waveform, frequency) may be varied as a result of the differentmeasurable results.

In one embodiment, the response evoked by stimulation signals (e.g.,electrical waveforms) that are generated by example apparatus andmethods may be analyzed with respect to frequency content or timeproperties. These signals include the evoked potential generateddirectly by a stimulus as well as the after-discharge observed followingthe evoked response. These evoked responses may be monitored or recordedfrom implanted electrodes or surface electroencephalography (EEG)electrodes. For example, the response evoked may have a first frequencycontent when no seizure is imminent but may have a second, differentfrequency content when a seizure is imminent. Similarly, the responseevoked may have a first time property when no seizure is imminent butmay have a second, different time property when a seizure is imminent.The time property may be, for example, how long it takes to evoke theresponse, the length of the evoked response, or other time-relatedproperties.

Table 1 shows results of a study performed on subjects with intractableepilepsy who were implanted with depth electrodes as part of a surgicalevaluation. There was no overt hippocampal pathology, includinghippocampal sclerosis, on their brain MRIs. The seizure semiology andscalp-recorded interictal epileptiform discharges and ictal EEGsuggested MTLE in all subjects.

Since neuropsychological testing found normal or only mildly-decreasedmemory scores, depth electrode evaluation was recommended to rule out anextra-hippocampal seizure onset, which would spare the non-lesionalhippocampus surgically, thus preserving memory. Therefore, implantedareas included the temporal neocortex, amygdala, and hippocampus, inaddition to areas known to be connected with the mesial temporalstructures. The choice of these areas was guided partly by the seizuresemiology, and included the insula in some subjects, temporal pole insome subjects, and the posterior cingulate gyms in some subjects. Inaddition, depth electrodes were implanted in the basal temporal,frontal, and temporo-occipital areas in smaller subsets of subjects. Thefornix electrodes were implanted in the corpus of the fornix in somesubjects, and in an area that is anterolateral to the splenium of thecorpus callosum where the crux of the fornix travels with fibers of thedorsal hippocampal commissure (the forno-dorso-commissural tract) inother subjects. The total number of electrodes to be implanted wasdecided according to clinical criteria. For research purposes, thetrajectory of a single clinically-indicated electrode probe that sampledthe temporoparietal or temporo-occipital cortex was modified to targetthe fornix medially.

After brain MRIs were obtained in the Leksell frame, the images wereexported to the iPlan workstation (Brainlab, Inc. Westchester, Ill.,USA) where electrode implantation was planned. The implantation targetswere chosen and the coordinates were determined before the electrodeswere advanced through drill twists to the target points underfluoroscopic guidance. The electrodes were platinum-iridium cylindersmeasuring 1.1 mm in diameter and 2.3 mm in length, evenly spaced at 5 mmintervals, and depth electrode probes contained 10-12 contacts (Adtech,Racine, Wis., USA). Other electrodes may be employed.

Following electrode implantation, the subjects were transferred to theEpilepsy Monitoring Unit and underwent continuous video-EEG monitoring.A head CT scan was obtained post-operatively and the locations of thedepth electrodes were verified by co-registration of pre-surgicalvolumetric brain MRI with postsurgical volumetric brain CT (Brainlab,Inc. Westchester, Ill., USA) according to anatomical fiducials, as shownin FIG. 1. EEG recordings were made using Nihon Kohden (Foothill Ranch,Calif., USA). EEG channels were amplified, filtered (0.1-300 Hz), andrecorded digitally with a sampling frequency of 1000 Hz.

The connectivity of the fornix with the hippocampus and posteriorcingulate region was confirmed by applying single pulse electricalstimulation to the fornix and averaging the evoked responses in otherregions. The pulses consisted of bipolar square waves applied to twocontiguous electrodes with a pulse width of 0.2 msec at a currentintensity of 8 mA/phase and a frequency of 1 Hz. Fifty pulses perelectrode pair were applied and the evoked potentials were averaged. Theraw EEG was initially visualized to exclude stimuli that includedartifacts. Both bipolar and referential montages were used to displaythe averaged responses in order to confirm the consistency of theresponses.

The Folstein mini-mental status examination (MMSE) was performed in allsubjects before stimulation was started. Four of the subjects hadanother baseline MMSE score documented in their charts 2-6 months beforeelectrode implantation. During the first four-hour stimulation session,a neurologist was present to monitor the EEG for seizures andafter-discharges and perform hourly neurological assessment, includingMMSE, for a total of three assessments per subject. Each assessment useda new set of three words to test registration and delayed recall. Eachset of words consisted of a state name in the U.S., a color, and anabstract quality, such as ‘honesty’. All dosages of antiepileptic drugs(AEDs) administered during the hospital stay were recorded, and subjectswho received AEDs less than two days prior to stimulation were excludedfrom the seizure analysis.

Fornix stimulation was performed using bipolar square waves with a pulsewidth of 0.2 msec, current intensity of 8 mA/phase, and stimulationfrequency of 5 Hz in all subjects. At 8 mA/phase, the charge density was20 microcoulombs (μC) per square centimeter, which is below the safemaximum. Stimulation occurred in four-hour sessions. Some subjectsunderwent one four-hour stimulation session, some subjects underwentthree sessions over three days, some subjects had two sessions over twodays, and some subjects underwent nine sessions. For the subjects whohad hippocampal seizure onset, the entire continuous EEG starting 1-2days before the first low frequency stimulation session and ending 1-2days after the last session was then reviewed, and the hippocampalspikes were counted and documented per hour of the day. These subjects'seizure times were also documented in order to study the effect of lowfrequency stimulation on seizures.

Generalized estimating equations (GEE) models were used to estimate theimpact of stimulation on seizure count and spike count. An exchangeablecorrelation matrix structure was used for outcomes to indicate that thedegree of similarity within subjects was comparable across subjects. Thelogit link function was used for seizure count, which is a binomialvariable (presence versus absence), and the identity link function forspike count and MMSE scores, since these are continuous variables.Seizure counts were analyzed using seizures per four hour block in the24-48 hours that preceded the first stimulation session and the sameduration that followed the last session for some subjects. Modelcoefficients for seizure count analysis were exponentiated to yield anodds ratio that approximated the relative likelihood of seizures duringand after stimulation versus before stimulation. Thus, “seizure odds”refers to a ratio describing the relative likelihood of a seizure duringand after stimulation versus before stimulation. Model coefficients forspike count and MMSE analysis were interpreted as change in numbers from‘during’ versus ‘before’ stimulation, that is, a negative coefficientwould indicate reduction. The Mann-Whitey U test was used to analyze theMMSE scores.

The hippocampal evoked responses to fornix stimulation showed an earlynegative deflection with a mean latency of 37±11 msec in all subjects.Subsequent components were seen less consistently. The initial responsefor some patients had a bifid morphology with the first negative peakoccurring between 24 and 37 msec, and the second negative peak occurringwithin 20 msec of the first peak. In other patients, a slow negativeresponse peaked between 150 and 166 ms. Some subjects had a laternegative bifid response with one peak at 200-229 and another at 241-250msec. In addition, one subject had a reverberating rhythm withadditional negative peaks at 300, 360, and 420 msec.

For the clinical purposes of ruling out seizure onset in regions withknown connectivity with the mesial temporal lobe, some subjectsunderwent implantation of depth electrodes in the posterior cingulategyms, and postoperative imaging confirmed electrode localization in thatregion. Stimulation of the fornix at 1 Hz resulted in evoked responsesin the posterior cingulate gyms in all subjects. In some subjects, theseresponses consisted of a late positive response at 187 msec. In onesubject, initial small negative peaks at 27 and 56 msec were followed bya late negative peak at 200 msec. The posterior cingulate response had alatency of 70 msec in the remaining two subjects, and was of positivepolarity in one subject and negative in another subject.

No seizures occurred during low frequency stimulation in patients withhippocampal epilepsy, but some seizures occurred during stimulation inpatients with extra-hippocampal epilepsy. Some subjects had additionaldocumented MMSE scores before implantation. In these subjects, thepre-implantation and post-implantation baseline scores were notdifferent (p=0.44). Data was entered into a GEE model that accounted forintra-individual and inter-individual differences. The results showedthat stimulation produced a significant increase in the MMSE score of0.82 points (P<0.001).

Analyzing the delayed recall component of the MMSE showed that out ofthree possible points, the average pre-stimulation score in the subjectswas 1.53±0.92, which increased to 2.27±0.67 during stimulation. Thus,the MMSE score improvement was largely due to improvement of the delayedrecall component. Comparing the baseline recall score that was obtainedafter electrode implantation with the first recall score obtained onehour through stimulation revealed no significant difference (p=0.26),but comparing the baseline with second and third recall scores obtainedduring stimulation showed a significant increase (p=0.038 and 0.01,respectively).

FIG. 3 illustrates hippocampal spike counts averaged per hour before,during, and after low-frequency stimulation. The spike count is reducedduring and even after low-frequency stimulation. The reduction in spikecount indicates the reduction of hyper-excitability of neural tissue.Overall, a reduction of hippocampal spikes by 36.4 spikes/hour (95%confidence interval of spike reduction 15.8-56.9, p=0.001), from abaseline of 58.1 spikes/hour to 21.7 spikes/hour was achieved duringstimulation. The spike reduction persisted for the subsequent four hours(p=0.05), before returning to baseline.

The seizure analysis included the period around stimulation whereantiepileptic medications were not changed (n=7, Table 1, FIG. 4). FIG.4 illustrates a scatter plot showing the seizures recorded before andafter stimulation. In FIG. 4, zero hour corresponds to the time duringwhich low frequency stimulation of the fornix was in progress. Theseizure counts included represent the number of seizures in the fortyeight hours that preceded the first session (−48, 0), and the number ofseizures that followed the last session (0, 48). No seizures occurredduring stimulation. The number of seizures after stimulation wasreduced. Seizure odds were reduced by 90.3% for up to two days followingstimulation.

Stimulation of a white matter tract can interfere with the spontaneousactivity of a relatively broader brain region. The fornix is a compactwhite matter tract and may be stimulated using one or more electrodes,which will synchronize, and may override spontaneous activity across thelength of the hippocampus as evidenced by the robust, short-latencyevoked responses recorded from the hippocampus. Direct stimulation ofthe hippocampus at both high (e.g., >10 Hz) or low (e.g., <1 Hz)frequencies can impair memory. However, stimulation of extra-hippocampalstructures within the memory circuit, such as the fornix or theentorhinal cortex, may enhance memory. This is associated withactivity-dependent regulation of hippocampal neurogenesis. Such effectshave been observed with high-frequency stimulation of the entorhinalcortex and other limbic targets such as the anterior thalamic nucleus.

Low frequency stimulation is attractive for clinical implementationsince the duty cycle of the stimulation is low, implying less electriccurrent injection with less charge density on target tissue andelectrodes and longer battery life. In one embodiment, when a seizurefocus is identified, a white matter tract that is intimately connectedto that focus may be identified (e.g., through tractography) andstimulated. As an example, seizure foci in perisylvian language areascan be treated by low frequency stimulation of parts of the arcuatefasciculus. In another embodiment, a closed-loop, feedback stimulationdetects and aborts hippocampal seizure episodes without inducing adverseeffects of continuous stimulation.

Some portions of the detailed descriptions that follow are presented interms of algorithms and symbolic representations of operations on databits within a memory. These algorithmic descriptions and representationsare used by those skilled in the art to convey the substance of theirwork to others. An algorithm is considered to be a sequence ofoperations that produce a result. The operations may include creatingand manipulating physical quantities that may take the form ofelectronic values. Creating or manipulating a physical quantity in theform of an electronic value produces a concrete, tangible, useful,real-world result.

It has proven convenient at times, principally for reasons of commonusage, to refer to these signals as bits, values, elements, symbols,characters, terms, numbers, and other terms. It should be borne in mind,however, that these and similar terms are to be associated with theappropriate physical quantities and are merely convenient labels appliedto these quantities. Unless specifically stated otherwise, it isappreciated that throughout the description, terms including processing,computing, and determining, refer to actions and processes of a computersystem, logic, processor, or similar electronic device that manipulatesand transforms data represented as physical quantities (e.g., electronicvalues).

Example methods may be better appreciated with reference to flowdiagrams. For simplicity, the illustrated methodologies are shown anddescribed as a series of blocks. However, the methodologies may not belimited by the order of the blocks because, in some embodiments, theblocks may occur in different orders than shown and described. Moreover,fewer than all the illustrated blocks may be required to implement anexample methodology. Blocks may be combined or separated into multiplecomponents. Furthermore, additional or alternative methodologies canemploy additional, not illustrated blocks.

FIG. 7 illustrates a method 700 associated with configuring aneuro-stimulation signal based on a desired therapeutic effect and theresponse the stimulation produced by applying the neuro-stimulationsignal evokes in a targeted area. Method 700 may include, at 710,applying an electrical waveform with a low frequency (e.g., less than 10Hz) to white matter in a human brain using an implanted electrode. Inone embodiment, the white matter is the forno-dorso-commissure (FDC).The FDC is an area anterolateral to the splenium of the corpus callosumwhere the crux of the fornix travels with fibers of the dorsalhippocampal commissure. In one embodiment, the implanted electrode is asingle electrode implanted unilaterally. In another embodiment, theimplanted electrode may be two electrodes implanted bilaterally.

In one embodiment, the electrical waveform is applied according to oneor more configurable properties. The configurable properties mayinclude, for example, the frequency at which the electrical waveform isapplied. In one embodiment, the frequency may be 10 Hz or less. Inanother embodiment, the frequency may be 2 Hz or less. Differentfrequencies may be employed. The one or more configurable properties mayalso include, for example, the type of waveform, the pulse width, thecurrent intensity, the current amplitude, the voltage amplitude, orother properties. In one example, the waveform is a sinusoidal waveform.In another example, the waveform is a bipolar square wave with a pulsewidth between 0.1 msec and 0.3 msec, a current intensity between 5mA/phase and 10 mA/phase, and a voltage amplitude between 1V and 10V.

Method 700 may also include, at 720, measuring a resulting electricalsignal in a target area in the brain. The target area is connected tothe white matter, innervated by the white matter, or can be activated bythe white matter. For example, when the area stimulated is the FDC, thetarget area may be the hippocampus, the posterior cingulate gyms, or theamygdala. Other target areas may be employed. The resulting electricalsignal is produced in response to applying the electrical waveform tothe white matter.

Various properties of the resulting electrical signal may be measured.Thus, measuring the resulting electrical signal at 720 may includemeasuring the amplitude of the electrical signal, measuring thefrequency content of the electrical signal, measuring the shape of theelectrical signal, or measuring a time property of the electricalsignal. The resulting electrical signal may have different properties atdifferent times. Thus, in one embodiment, measuring the electricalsignal occurs between 50 ms and 250 ms after the end of the applicationof the electrical waveform. In different embodiments, the electricalsignal may be measured using an implanted electrode or surface EEGelectrode.

Method 700 may also include, at 730, selectively updating a member ofthe one or more configurable properties until applying the electricalwaveform produces a desired electrical signal. In one embodiment,producing the desired electrical signal reduces hyper-excitability ofneural tissue in the target area. Reducing hyper-excitability may inturn reduce hippocampal spikes, reduce seizures, or reduced otherundesired events.

In one embodiment, method 700 may include computing an impedance oftissue in the target region based on the electrical signal. The one ormore configurable properties may then be updated based on the impedance.

The electrical waveform may be configured and applied to achievedifferent results or therapeutic effects. In one example, the electricalwaveform may be configured and applied to produce an electrical signalthat will reduce hyper-excitability of neural tissue in the target areain an amount sufficient to prevent an epileptic seizure. In oneembodiment, the electrical waveform may be configured and applied toproduce an electrical signal that prevents an epileptic seizureoriginating in the mesial temporal lobe.

The stimulation provided by the electrical waveform may be configuredand reconfigured to produce an electrical signal that reduceshippocampal spikes by at least ten spikes per hour. Different waveformsmay be produced to reduce hippocampal spikes by other amounts. Reducinghyper-excitability of neural tissue in a target region may reduceseizure odds by at least ninety percent. The stimulation may produceresults during a stimulation session and even after a stimulationsession. In one embodiment, the electrical waveform may be configuredand applied to produce an electrical signal that reduces hippocampalspikes by at least fifty percent while the method is being performed. Inanother embodiment, the method may be performed for a time periodsufficient to produce a carryover effect that reduces hyper-excitabilityof neural tissue in the target area after the method is no longer beingperformed. In different embodiments, the carryover effect may last forfour hours, twenty four hours, or even longer.

In one embodiment, the stimulation may be targeted at recall. Thus, inone embodiment, the electrical waveform may be configured and applied toreduce hyper-excitability of neural tissue in the target area in anamount sufficient to improve recall in patients having Alzheimer's,hippocampal sclerosis, autism, schizophrenia, senile dementia, orstroke.

While FIG. 7 illustrates various actions occurring in serial, it is tobe appreciated that various actions illustrated in FIG. 7 could occursubstantially in parallel. By way of illustration, a first process couldcontrol applying stimulation, a second process could monitor or recordevoked potentials, and a third process could reconfigure stimulationparameters based on the evoked potentials and a desired therapeuticeffect. While three actions are described, it is to be appreciated thata greater and/or lesser number of actions could be employed.

FIG. 8 illustrates an apparatus 800. Apparatus 800 includes astimulation logic 810 that is configured to control the application of aneuro-stimulation signal to the forno-dorso-commissure (FDC) 825 duringa stimulation session. In one embodiment, the stimulation logic 810controls the application of the neuro-stimulation signal to the FDC 825based, at least in part, on a characteristic of the electrical signaland on a desired therapeutic effect. Thus, a feedback loop may be set upwhere the stimulation logic 810 produces an effect at the target 835,the effect is analyzed, and the stimulation logic 810 is reconfiguredbased on the analysis.

The stimulation logic 810 may control the neuro-modulation signal withrespect to frequency, amplitude, wave form, pulse width, currentamplitude, voltage amplitude, or other properties. For example, thestimulation logic 810 may produce sinusoidal waves, square waves, orother waveforms having different frequencies, amplitudes, and pulsewidths.

Apparatus 800 also includes a first electrode 820 that is connected tothe stimulation logic 810. The first electrode 820 may be configured toapply the neuro-stimulation signal to the FDC 825. While a singleelectrode 820 is illustrated, in one embodiment, stimulation logic 810may provide a neuro-stimulation signal to two or more electrodes. In oneembodiment, the neuro-modulation signal has a frequency of less thanfive hertz. Other frequencies may be employed.

Apparatus 800 also includes a second electrode 830 that is connected tothe stimulation logic 810. The second electrode 830 is configured todetect an electrical signal evoked in a target neural tissue 835 inresponse to the application of the neuro-stimulation signal. The targetneural tissue 835 is connected to, innervated by, or can be activated bythe FDC. The target neural tissue 835 may be, for example, thehippocampus, the posterior cingulate gyms, or the amygdala. Othertargets may be employed. While a single electrode 830 is illustrated,one or more electrodes may monitor or record potentials evoked in thetarget 835.

The characteristic of the electrical signal evoked in the target neuraltissue may be analyzed with respect to, for example, amplitude,frequency, frequency content, shape, a time at which the electricalsignal was detected, or a length of time during which the electricalsignal was detected. Different desired therapeutic effects may beachieved when different characteristics of the electrical signal fallwithin certain ranges or have certain properties.

The therapeutic effects may be related to a property of the tissue(e.g., hyper-excitability), an effect noticed in a portion of the brain(e.g., hippocampal spikes), or an over-arching effect (e.g., seizure).Thus, in one example, the desired therapeutic effect is a ten percentreduction in hyper-excitability of the target neural tissue. Otherreductions may be sought. In another example, the desired therapeuticeffect is a fifty percent reduction in hippocampal spikes. Otherreductions may be sought. In yet another example, the desiredtherapeutic effect is reducing seizure odds by seventy five percent.Other reductions may be sought. In yet another embodiment, the desiredtherapeutic effect is improving memory recall in a patient havingAlzheimer's, hippocampal sclerosis, autism, schizophrenia, seniledementia, or stroke.

The stimulation logic 810 may provide stimulation during a stimulationsession and a desired therapeutic effect may be achieved during thestimulation session. In one embodiment, the stimulation logic 810 may beconfigured to cause the neuro-stimulation signal to be applied to theFDC 825 for a period of time sufficient to produce the therapeuticeffect after the stimulation session has ended.

FIG. 9 illustrates an apparatus 900. Apparatus 900 includes aneuro-stimulation circuit 910 that is configured to produce adynamically re-configurable neuro-stimulation signal having a frequencyof less than 2 Hz. Apparatus 900 also includes one or moreneuro-stimulation electrodes (e.g., electrode 920, electrode 922) thatare implanted unilaterally or bilaterally and configured for applyingthe neuro-stimulation signal to white matter 925 (e.g.,forno-dorso-commissure (FDC)).

Apparatus 900 also includes one or more monitoring electrodes (e.g.,electrode 930, electrode 932) that are configured to detect anelectrical potential evoked in a target neural tissue 935 in response tothe neuro-stimulation signal being applied to the white matter 925.Since apparatus 900 intends to reconfigure the neuro-stimulation circuit910 based on a potential evoked by applying the neuro-stimulation signalto the white matter 925, the target neural tissue 935 is connected to,innervated by, or can be activated by the white matter 925.

Apparatus 900 also includes a feedback circuit 940 that is configured tocontrol the neuro-stimulation circuit 910. The neuro-stimulation circuit910 is controlled based on the detected electrical potential and adesired therapeutic effect. The feedback circuit 940 controls theneuro-stimulation circuit 910 to dynamically reconfigure theneuro-stimulation signal.

TABLE 1 Age at Subject Seizure Seizure Focus No. Handedness Age OnsetLocalization Seizure Semiology 1 Right 34 1 Right hippocampus Epigastricsensation, alteration of awareness with automatisms 2 Right 56 46 Lefthippocampus Epigastric sensation, alteration of awareness 3 Right 23 14Left hippocampus Psychic aura, alteration of awareness with automatisms4 Right 38 35 Right hippocampus Psychic aura, gustatory experience,alteration of awareness 5 Right 51 39 Left hippocampus Alteration ofawareness with automatisms 6 Right 28 22 Right hippocampus Cephalicaura, alteration of awareness, left version 7 Right 39 29 Lefthippocampus Alteration of awareness with automatisms, right version 8Ambidextrous 46 17 Left temporal Psychic aura, aphasic seizure neocortex9 Right 37 1 Extrahippocampal Cephalic aura, alteration of awareness 10Right 39 19 Extrahippocampal Cephalic aura, alteration of awareness withautomatisms 11 Right 55 30 Right hippocampus Psychic aura, alteration ofawareness with automatisms Days before Days before first, and first, andafter after last, last, stimulation WMS - WMS - Intracarotid stimulationincluded in Subject Brain MRI verbal visual Amobarbital with no AEDspike and No. Findings delayed delayed Procedure changes seizureanalysis 1 Normal 120 72 Left −1, 2 −1, 1 

Language and memory 2 Normal 102 115 Left −8, 9 −2, 2 Language,bilateral memory 3 Normal 108 103 — −2, 2 −2, 2 4 Normal 124 132 — −4, 1−1, 1 5 Non-specific 71 84 Left −5, 1 −1, 1 white matter Language,changes bilateral memory 6 Normal 99 94 Left −1*, 4  −2, 2 Language,bilateral memory 7 Normal 83 78 Left −2, 2 −2, 2 Language, bilateralmemory 8 Left 99 115 Left −1, 2 hippocampus is Language, smaller thanthe bilateral right memory hippocampus, without signal changes 9Increased T2 77 81 Left −3, 1 signal within the Language, middle andbilateral posterior memory hippocampus bilaterally 10 Non-enhancing 94109 Left −1, 1 left entorhinal Language, and amygdala bilateral T2/FLAIRmemory hyperintensity 11 Normal 94 97 Left −3*, 4  −2, 2 Language,bilateral memory WMS, Wechsler Memory Scale AED, antiepileptic drug *AnAED was discontinued

 Included in spike, but not seizure analysis

The following includes definitions of selected terms employed herein.The definitions include various examples and/or forms of components thatfall within the scope of a term and that may be used for implementation.The examples are not intended to be limiting. Both singular and pluralforms of terms may be within the definitions.

References to “one embodiment”, “an embodiment”, “one example”, “anexample”, and other similar exemplary language indicate that theembodiment(s) or example(s) so described may include a particularfeature, structure, characteristic, property, element, or limitation,but that not every embodiment or example necessarily includes thatparticular feature, structure, characteristic, property, element orlimitation. Furthermore, repeated use of the phrase “in one embodiment”does not necessarily refer to the same embodiment, though it may.

“Logic”, as used herein, includes but is not limited to hardware,firmware, software in execution on a machine, and/or combinations ofeach to perform a function(s) or an action(s), and/or to cause afunction or action from another logic, method, and/or system. Logic mayinclude a software controlled microprocessor, a discrete logic (e.g.,ASIC), an analog circuit, a digital circuit, a programmed logic device,a memory device containing instructions, and other entities. Logic mayinclude one or more gates, combinations of gates, or other circuitcomponents. Where multiple logical logics are described, it may bepossible to incorporate the multiple logical logics into one physicallogic. Similarly, where a single logical logic is described, it may bepossible to distribute that single logical logic between multiplephysical logics.

An “operable connection”, or a connection by which entities are“operably connected”, is one in which signals, physical communications,and/or logical communications may be sent and/or received. An operableconnection may include a physical interface, an electrical interface,and/or a data interface. An operable connection may include differingcombinations of interfaces and/or connections sufficient to allowoperable control. For example, two entities can be operably connected tocommunicate signals to each other directly or through one or moreintermediate entities (e.g., processor, operating system, logic,software). Logical and/or physical communication channels can be used tocreate an operable connection.

“Signal”, as used herein, includes but is not limited to, electricalsignals, optical signals, analog signals, digital signals, data,computer instructions, processor instructions, messages, a bit, a bitstream, and other items, that can be received, transmitted and/ordetected.

While example systems, methods, and other embodiments have beenillustrated by describing examples, and while the examples have beendescribed in considerable detail, it is not the intention of theapplicants to restrict or in any way limit the scope of the appendedclaims to such detail. It is, of course, not possible to describe everyconceivable combination of components or methodologies for purposes ofdescribing the embodiments described herein. Therefore, the invention isnot limited to the specific details, the representative apparatus, andillustrative examples shown and described. Thus, this application isintended to embrace alterations, modifications, and variations that fallwithin the scope of the appended claims.

To the extent that the term “includes” or “including” is employed in thedetailed description or the claims, it is intended to be inclusive in amanner similar to the term “comprising” as that term is interpreted whenemployed as a transitional word in a claim.

To the extent that the term “or” is employed in the detailed descriptionor claims (e.g., A or B) it is intended to mean “A or B or both”. Whenthe applicants intend to indicate “only A or B but not both” then theterm “only A or B but not both” will be employed. Thus, use of the term“or” herein is the inclusive, and not the exclusive use. See, Bryan A.Gamer, A Dictionary of Modern Legal Usage 624 (2d. Ed. 1995).

To the extent that the phrase “one or more of, A, B, and C” is employedherein, (e.g., a data store configured to store one or more of, A, B,and C) it is intended to convey the set of possibilities A, B, C, AB,AC, BC, ABC, AAA, AAB, AABB, AABBC, AABBCC, (e.g., the data store maystore only A, only B, only C, A&B, A&C, B&C, A&B&C, A&A&A, A&A&B,A&A&B&B, A&A&B&B&C, A&A&B&B&C&C). It is not intended to require one ofA, one of B, and one of C. When the applicants intend to indicate “atleast one of A, at least one of B, and at least one of C”, then thephrasing “at least one of A, at least one of B, and at least one of C”will be employed.

Throughout this specification and the claims that follow, unless thecontext requires otherwise, the words ‘comprise’ and ‘include’ andvariations such as ‘comprising’ and ‘including’ will be understood to beterms of inclusion and not exclusion. For example, when such terms areused to refer to a stated integer or group of integers, such terms donot imply the exclusion of any other integer or group of integers.

1-30. (canceled)
 31. An apparatus, comprising: a stimulation logicconfigured to control the application of a neuro-stimulation signal witha frequency of less than ten Hertz to the forno-dorso-commissure (FDC)of a human brain during a stimulation session based and reconfigure theneuro-stimulation signal based on a characteristic of a feedback signal;a stimulating electrode connected to the stimulation logic andconfigured to apply the neuro-stimulation signal to the FDC; and arecording electrode connected to the stimulation logic and configured tosend the feedback signal to the stimulation logic based on a detectedelectrical signal evoked in the target neural tissue in response to theapplication of the neuro-stimulation signal, wherein the target neuraltissue is connected to, innervated by, or activated by the FDC.
 32. Theapparatus of claim 1, wherein the frequency is less than five Hertz. 33.The apparatus of claim 1, wherein the frequency is less than two Hertz.34. The apparatus of claim 1, wherein stimulation logic is configured tocompare the characteristic of the feedback signal to a desiredtherapeutic effect to make the reconfiguration of the neuro-stimulationsignal, wherein the desired therapeutic effect comprises an increase ina threshold of action potential firing in a target neural tissue by longterm depression or an increase in gamma-aminobutyric acid (GABA)mediated inhibition in the target neural tissue;
 35. The apparatus ofclaim 1, where the stimulation logic is configured to reconfigure theneuro-modulation signal by modulating a frequency, an amplitude, a waveform, a pulse width, a current amplitude, or a voltage amplitude of theneuro-modulation signal based on the characteristic of the feedbacksignal and the desired therapeutic effect.
 36. The apparatus of claim 1,where the characteristic of the feedback signal comprises an amplitude,a frequency, a frequency content, a shape, a time at which theelectrical signal is detected, or a length of time during which theelectrical signal is detected.
 37. The apparatus of claim 1, where thedesired therapeutic effect is at least one of: at least a ten percentreduction in hyper-excitability of the target neural tissue; at least afifty percent reduction in hippocampal spikes in the human brain; andreducing seizure odds in the human brain by at least seventy fivepercent.
 38. The apparatus of claim 1, where the desired therapeuticeffect is an improvement in memory recall in a patient with Alzheimer's,hippocampal sclerosis, autism, schizophrenia, senile dementia, orstroke.
 39. The apparatus of claim 1, where the stimulation logic causesthe neuro-stimulation signal to be applied to the FDC for a period oftime sufficient to produce a carryover therapeutic effect in which thetherapeutic effect extends for a time period after the stimulationsession has ended.
 40. The apparatus of claim 1, where the target neuraltissue is located in the hippocampus, the posterior cingulate gyrus, orthe amygdala.
 41. The apparatus of claim 1, wherein the stimulationlogic comprises: a neuro-stimulation circuit configured to produce theneuro-stimulation signal; and a feedback circuit configured to controlthe neuro-stimulation circuit to reconfigure the neuro-stimulationsignal based on the characteristic of the feedback signal and thedesired therapeutic effect.
 42. The apparatus of claim 1, wherein thestimulating electrode comprises one or more neuro-stimulation electrodesimplanted unilaterally or bilaterally in the human brain to apply theneuro-stimulation signal to the FDC.
 43. The apparatus of claim 1,wherein the recording electrode comprises one or more monitoringelectrodes configured to detect an electrical potential evoked in atarget neural tissue in response to the neuro-stimulation signal beingapplied to the FDC, wherein the feedback signal is based on the detectedelectrical potential.
 44. The apparatus of claim 1, wherein theneuro-stimulation signal comprises a bipolar square wave or a sinusoidalwave, wherein the pulse width is between 0.1 msec and 0.3 msec, thecurrent intensity is between 5 mA/phase and 10 mA/phase, and the voltageamplitude is between 0.1V and 10V pp.
 45. A method, comprising: applyinga stimulation signal with a frequency of less than 10 Hz to white matterin a human brain using an implanted stimulating electrode, where theelectrical waveform is applied according to one or more configurableproperties; measuring an electrical signal in a target area in the humanbrain produced in response to stimulation of the white matter using arecording electrode, wherein the target area is connected to the whitematter; and updating a configurable property of the stimulation signaluntil applying the stimulation signal produces a desired electricalsignal that reduces hyper-excitability of neural tissue in the targetarea by increasing a threshold of action potential firing in the neuraltissue in the target area by long term depression or by increasinggamma-aminobutyric acid (GABA) mediated inhibition in the neural tissuein the target area, wherein the white matter is theforno-dorso-commissure, where the forno-dorso-commissure is an areaanterolateral to the splenium of the corpus callosum where the crux ofthe fornix travels with fibers of the dorsal hippocampal commissure. 46.A system, comprising: a stimulation logic comprising: aneuro-stimulation circuit configured to produce a neuro-stimulationsignal with a frequency of less than 10 Hz; and a feedback circuitconfigured to control the neuro-stimulation circuit to reconfigure aparameter of the neuro-stimulation signal based on the characteristic ofa feedback signal; a stimulating electrode connected to theneuro-stimulation circuit and configured to apply the neuro-stimulationsignal to the forno-dorso-commissure (FDC); and a recording electrodeconnected to the feedback circuit and configured to detect an electricalsignal evoked in the target neural tissue in response to the applicationof the neuro-stimulation signal and send the feedback signal to thefeedback circuit, wherein the target neural tissue is connected to,innervated by, or activated by the FDC.
 47. The system of claim 16,wherein the recording electrode detects the electrical signal between 50ms and 250 ms after the end of the application of the electricalwaveform.
 48. The system of claim 16, wherein the feedback circuitcomputes an impedance of tissue in the target region based on thefeedback signal, and wherein the neuro-stimulation circuit reconfiguresthe parameter of the neuro-stimulation signal based on the impedance.49. The system of claim 16, wherein the stimulating electrode appliesthe neuro-stimulation signal to the FDC for a time period sufficient toproduce a carryover effect that reduces hyper-excitability of neuraltissue in the target area after the neuro-stimulation signal is nolonger applied.
 50. The system of claim 19, wherein the stimulatingelectrode applies the neuro-stimulating signal to the FDC for a timeperiod sufficient to produce the carryover effect for at least fourhours.